Method for synthesizing benzo 12-membered lactone compound through [7 +5] cycloaddition reaction

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a benzo 12-membered lactone compound through [7 + 5] cycloaddition reaction. According to the method, 1-allyl carbonate-2-alcohol-based benzene as shown in a formula 1 and succinic anhydride derived power-deficient olefin as shown in a formula 2 are used as raw materials, palladium and phosphine ligands are used as catalysts, the benzo12-membered lactone compound as shown in a formula 3 is prepared through reaction, and the reaction equation is as follows: # imgabs0 #. The method has the advantages that the catalyst is cheap and easy to obtain, the yield is high, the substrate compatibility is good, and the method is suitable for industrial production. The reaction conditions are mild, and high dilution conditions are not needed.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing benzododecaproide through a [7+5] cycloaddition reaction. Background Art

[0002] Dodecalactones are widely present in natural products with important physiological activities and are the core structure of their functions (Shen, Weiyun, et al. "Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities." European journal of medicinal chemistry 97 (2015): 747-777.). For example, Lactimidomycin is a compound containing glutarimide and dodecalactone isolated from Streptomyces. It is an effective eukaryotic translation elongation inhibitor, has effective anti-proliferation effects on tumor cell lines, and selectively inhibits protein translation. Lasiodiplodin is isolated from Euphorbias plendens and is an anti-leukemia macrolide. There are more than 200 natural products containing dodecalactone skeletons. Therefore, it is of great research value to develop an efficient synthetic route to prepare dodecalactones with diverse structures.

[0003]

[0004] At present, the method for synthesizing twelve-membered lactone compounds is mainly through the intramolecular ring-closing strategy: including macrocyclic lactonization, ring-closing olefin metathesis, etc. (Cordes M, Kalesse M. Synthesis of 12-to 16-Membered-Ring Lactones [J]. Synthesis of Saturated Oxygenated Heterocycles II: 7-to 16-Membered Rings, 2014: 369-427.). This type of method has some defects: 1) The substrate synthesis is lengthy and cumbersome, and the functional groups need to be carefully installed to meet the cyclization reaction, and the substrate diversity is poor; 2) Excessive activation reagents are required, resulting in a large number of by-products; 3) A highly diluted reaction concentration is required to reduce intermolecular polymerization side reactions, resulting in a large amount of waste solvent. Therefore, the intramolecular ring-closing strategy has many limitations in industrial application.

[0005] In summary, the development of an efficient, low-waste, and structure-rich method for preparing twelve-membered lactone compounds has important application prospects. Summary of the invention

[0006] The present invention aims to provide an efficient preparation method of a benzo dodecalactone compound, wherein the method uses 1-allyl carbonate-2-olbenzene 1 and an electric-deficient olefin 2 derived from succinic anhydride as raw materials to synthesize the benzo dodecalactone under palladium and ligand catalysis. The method has high yield, good substrate compatibility, no need to dilute the concentration, mild reaction, and provides a simple, cheap and efficient way for the synthesis of benzo dodecalactone.

[0007] A method for synthesizing benzododecaproide via a [7+5] cycloaddition reaction comprises the following steps: using substituted 1-allyl carbonate-2-olbenzene 1 and an electric-deficient olefin 2 derived from succinic anhydride as raw materials, reacting in the presence of Pd(0) and a phosphine ligand to obtain benzododecaproide 3, and the reaction equation is as follows:

[0008]

[0009] Wherein, R is selected from hydrogen, aryl, and alkyl.

[0010] In some preferred embodiments, R is selected from hydrogen, phenyl, p-methylphenyl, methyl, ethyl, allyl, phenylethynyl.

[0011] According to the synthesis method of the present invention, the reaction temperature of the method is -10°C-60°C; preferably, the temperature is 25°C.

[0012] According to the synthesis method of the present invention, the reaction solvent of the method is tetrahydrofuran, dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, ethyl acetate; preferably, the reaction solvent is tetrahydrofuran.

[0013] According to the synthesis method of the present invention, the reaction time of the method is 2h-36h; preferably, the reaction time is 12h.

[0014] The inventors found that when the equivalent ratio of 1-allyl carbonate-2-olbenzene 1 to the power-deficient olefin 2 derived from succinic anhydride was 1:1, the catalytic ability of the combination of palladium source Pd(OAc)2, Pd2(dba)3 and ligand PPh3 was investigated respectively. The catalytic ability of Pd2(dba)3 as the palladium source was the best, and the yield of product 3 was the best; then Pd2(dba)3 was fixed as the palladium source, and other phosphine ligands were investigated. The reaction with (4-CF3Ph)3P as the ligand was the best. Reducing the amount of catalyst resulted in poor conversion.

[0015] According to the synthesis method of the present invention, the reaction palladium source of the method is Pd(OAc)2, Pd2(dba)3, and the ligand is PPh3, (4-FPh)3P, (4-CF3Ph)3P, (3-FPh)3, (4-ClPh)3P. Preferably, the reaction palladium source is Pd2(dba) 3, The ligand is (4-CF3Ph)3P.

[0016] According to the synthesis method of the present invention, the molar ratio of the 1-allyl carbonate-2-olbenzene 1, the succinic anhydride-derived electric-deficient olefin 2, the palladium source and the ligand is 1:0.5-2:0.01-0.1:0.04-0.4. Preferably, the molar ratio of the 1-allyl carbonate-2-olbenzene 1, the succinic anhydride-derived electric-deficient olefin 2, the palladium source and the ligand is 1:1:0.05:0.2.

[0017] In another aspect, the present invention provides a compound prepared using the method of the present invention, the compound being selected from:

[0018] Specific embodiments Specific embodiments

[0020] Example 1 Preparation of benzo dodecalactone 3a

[0021] In a 10mL vacuum tube, Pd2(dba)3 (4.6mg, 5mol%) and (4-CF3Ph)3P (9.3mg, 20mol%) were weighed. Nitrogen was replaced three times, and then 1mL of dry tetrahydrofuran was added, stirred for half an hour, 1-allyl carbonate-2-olbenzene 1a (26.4mg, 0.1mmol) and succinic anhydride-derived electric-deficient olefin 2 (24.2mg, 0.1mmol), stirred at room temperature for 12 hours. The reaction was tracked by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo, and 33.8mg of white solid 3a was obtained by column chromatography, with a yield of 87%. mp108-111℃; 1H NMR (600MHz, CDCl3): δ (ppm) 7.38-7.30 (m, 2H), 7.27-7.21 (m, 1H), 7.20 (d, J = 7.2Hz, 1H), 6.39 (d, J = 15.6Hz, 1H), 5.95 (dt, J = 15.6, 7.8Hz, 1H 13C NMR (150MHz, CDCl3): δ (ppm) 203.5, 171.0, 167.2, 138.6, 135.1, 132.5, 129.4, 129.2, 127. 4,127.3,125.2,69.7,66.3,62.2,39.1,37.9,29.3,13.9,13.9; HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C21H24O7Na + 411.1414; Found 411.1423.

[0022] Example 2 Benzododecaproic acid 3b

[0023] Pd2(dba)3 (4.6 mg, 5 mol%) and (4-CF3Ph)3P (9.3 mg, 20 mol%) were weighed into a 10 mL vacuum tube. The mixture was replaced with nitrogen three times, and then 1 mL of dry tetrahydrofuran was added. The mixture was stirred for half an hour. 1-allyl carbonate-2-olbenzene 1b (28.0 mg, 0.1 mmol) and succinic anhydride-derived electric-deficient olefin 2 (24.2 mg, 0.1 mmol) were stirred at room temperature for 12 hours. The reaction was followed by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo and column chromatography was performed to obtain 35.4 mg of colorless oil 3b with a yield of 88%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.33 (d, J = 7.2Hz, 1H), 7.28 (dd, J = 6.0, 2.4Hz, 1H), 7.26-7.22 (m, 2H), 6.62 (s, 1H), 5.95-5.85 (m, 2H), 4.2 5(dd,J=11.4,7.2Hz,4H),3.18-3.07(m,2H),3.08-2.99(m,2H),2.71-2.57(m,2H),1.65(d,J=6.6Hz,3H),1.28(dt,J=10.2,7.2Hz,6H); 13C NMR (150MHz, CDCl3): δ (ppm) 202.6,170.5,167.2,167.1,137.3,137.0,134.7,128.4,128.2,127.4,1 26.4,125.2,72.0,70.1,62.2,62.2,38.2,38.1,28.9,19.38,14.0,13.9; HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C22H26O7Na + 425.1571; Found 425.1579.

[0024] Example 3 Benzododecaproic acid 3c

[0025] Pd2(dba)3 (4.6 mg, 5 mol%) and (4-CF3Ph)3P (9.3 mg, 20 mol%) were weighed into a 10 mL vacuum tube. The mixture was replaced with nitrogen three times, and then 1 mL of dry tetrahydrofuran was added. The mixture was stirred for half an hour. 1-allyl carbonate-2-olbenzene 1c (29.2 mg, 0.1 mmol) and succinic anhydride-derived electric-deficient olefin 2 (24.2 mg, 0.1 mmol) were stirred at room temperature for 12 hours. The reaction was followed by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo and column chromatography was performed to obtain 33.7 mg of colorless oil 3c with a yield of 88%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.31 (dd, J=7.2, 1.8Hz, 1H), 7.26-7.17 (m, 2H), 7.13 (dd, J=7 .8,1.8Hz,1H),6.77(d,J=15.6Hz,1H),5.91-5.81(m,1H),5.61(t,J=7.2Hz,1H),4.30-4.2 1(m,4H),3.20-3.10(m,2H),3.12-3.04(m,1H),2.98(dd,J=13.8,9.6Hz,1H),2.75-2.62( m,2H),2.12-1.98(m,1H),1.95-1.83(m,1H),1.27(q,J=7.2Hz,6H),0.94(t,J=7.2Hz,3H); 13C NMR (150MHz, CDCl3): δ (ppm) 201.8,170.3,167.4,167.3,136.4,136.4,135.1,128.3,128.1,127.8, 127.2,124.9,78.8,70.3,62.2,62.2,38.1,37.1,28.2,27.8,13.9,10.6; HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C23H28O7Na + 439.1727; Found 439.1736.

[0026] Example 4 Benzododecaproic acid 3d

[0027] Pd2(dba)3 (4.6 mg, 5 mol%) and (4-CF3Ph)3P (9.3 mg, 20 mol%) were weighed into a 10 mL vacuum tube. The mixture was replaced with nitrogen three times, and then 1 mL of dry tetrahydrofuran was added. The mixture was stirred for half an hour. 1-allyl carbonate-2-olbenzene 1d (30.8 mg, 0.1 mmol) and succinic anhydride-derived electric-deficient olefin 2 (24.2 mg, 0.1 mmol) were stirred at room temperature for 12 hours. The reaction was followed by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo and column chromatography was performed to obtain 28.0 mg of colorless oil 3d, with a yield of 65%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.31 (dd, J = 7.8, 1.8Hz, 1H), 7.27-7.17 (m, 2H), 7.15 (dd, J=7.8,1.8Hz,1H),6.76(d,J=15.6Hz,1H),5.92-5.84(m,1H),5.78(t,J=7.2Hz,1H),5 .77-5.68(m,1H),5.14-5.05(m,2H),4.29-4.21(m,4H),3.21-3.03(m,3H),2.99(dd,J =13.8,9.0Hz,1H),2.82-2.74(m,1H),2.71-2.59(m,3H),1.27(dt,J=10.2,7.2Hz,6H); 13CNMR (150MHz, CDCl3): δ (ppm) 201.9,170.1,167.3,167.3,136.5,136.0,135.0,133.3,128.4,128.3,127 .7,127.2,125.2,118.2,76.1,70.3,62.2,62.2,39.0,38.0,37.,28.27,13.9; HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C24H28O7Na + 451.1727; Found 451.1734.

[0028] Example 5 Benzododecaproide 3e

[0029] Pd2(dba)3 (4.6 mg, 5 mol%) and (4-CF3Ph)3P (9.3 mg, 20 mol%) were weighed into a 10 mL vacuum tube. The mixture was replaced with nitrogen three times, and then 1 mL of dry tetrahydrofuran was added. The mixture was stirred for half an hour. 1-allyl carbonate-2-olbenzene 1e (34.0 mg, 0.1 mmol) and succinic anhydride-derived electric-deficient olefin 2 (24.2 mg, 0.1 mmol) were stirred at room temperature for 12 hours. The reaction was followed by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo and column chromatography was performed to obtain 35.7 mg of colorless oil 3e with a yield of 77%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.39-7.32 (m, 3H), 7.33-7.25 (m, 4H), 7.18 (td, J = 7.8 ,1.2Hz,1H),6.93(d,J=7.8Hz,1H),6.84(s,1H),6.54(d,J=15.6Hz,1H),5.92(dt, J=15.6,7.8Hz,1H),4.31-4.20(m,4H),3.17(dd,J=7.2,4.2Hz,2H),3.03(dt,J=7. 8,1.2Hz,2H),2.83-2.74(m,1H),2.71-2.64(m,1H),1.28(dt,J=10.2,7.2Hz,6H); 13C NMR (150MHz, CDCl3): δ (ppm) 202.7, 170.1, 167.2, 167.1, 138.5, 137.6, 136.3, 134.9, 128.9, 128.7, 128.5, 128. 1,127.8,127.2,126.7,125.2,77.0,70.0,62.2,62.2,38.3,38.3,28.7,14.0,13.9; HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C27H28O7Na + 487.1727; Found 487.1735.

[0030] Example 6 Benzododecaproide 3f

[0031] In a 10mL vacuum tube, Pd2(dba)3 (4.6mg, 5mol%) and (4-CF3Ph)3P (9.3mg, 20mol%) were weighed. Nitrogen was replaced three times, and then 1mL of dry tetrahydrofuran was added. Stir for half an hour, 1-allyl carbonate-2-olbenzene 1f (35.4mg, 0.1mmol) and succinic anhydride-derived electric-deficient olefin 2 (24.2mg, 0.1mmol) were stirred at room temperature for 12 hours. The reaction was tracked by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo and column chromatography was performed to obtain 40.3mg of colorless oil 3f, with a yield of 84%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.34 (d, J = 7.8Hz, 1H), 7.28 (t, J = 8.4Hz, 1H), 7.17 ( dd,J=11.4,4.8Hz,5H),6.93(d,J=7.8Hz,1H),6.81(s,1H),6.55(d,J=15.6Hz,1 H),5.92(dt,J=15.6,7.8Hz,1H),4.33-4.18(m,4H),3.16(t,J=5.4Hz,2H),3.02 (d,J=7.8Hz,2H),2.79-2.64(m,2H),2.35(s,3H),1.28(dt,J=11.4,7.2Hz,6H); 13C NMR (150MHz, CDCl3): δ (ppm) 202.7,170.1,167.2,167.1,137.5,136.5,135.5,135.0,129.2,128.8,128.6,128 .1,127.2,126.8,125.1,76.9,70.0,62.2,62.2,38.3,38.3,28.8,21.2,14.0,14.0; HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C28H30O7Na + 501.1884;Found 501.1891.

[0032] Example 7 Benzododecaproic acid 3g

[0033] In a 10mL vacuum tube, Pd2(dba)3 (4.6mg, 5mol%) and (4-CF3Ph)3P (9.3mg, 20mol%) were weighed. Nitrogen was replaced three times, and then 1mL of dry tetrahydrofuran was added, stirred for half an hour, 1-allyl carbonate-2-olbenzene 1g (36.4mg, 0.1mmol) and succinic anhydride derived electric-deficient olefin 2 (24.2mg, 0.1mmol), stirred at room temperature for 12 hours. The reaction was tracked by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo, and 38.3mg of colorless oil was obtained by column chromatography, with a yield of 78%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.68 (d, J = 7.8Hz, 1H), 7.53-7.48 (m, 2H), 7.39-7.33 (m, 2H), 7.36-7.27 (m, 4H), 6.69 (d, J = 15.6Hz, 1H), 6.54 (s,1H),6.07-5.78(m,1H),4.31-4.21(m,4H),3.22-3.04(m,3H),3.01(dd,J=13.8,8.4Hz,1H),2.74-2.63(m,2H),1.28(q,J=7.2Hz,6H); 13 C NMR (150MHz, CDCl3): δ (ppm) 202.8, 169.9, 167.2, 167.1, 137.6, 134.2, 133.0, 132.0, 129.5, 128.8, 128.3, 128.1, 128 .0,127.5,126.0,122.1,88.7,84.1,69.9,65.7,62.3,62.2,38.6,38.2,29.1,14.0,13.9; HRMS(ESI-TOF)m / z:[M+Na] +Calcd for C29H28O7Na + 511.1727; Found 511.1735.

[0034] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing a benzo dodecalactone compound by a [7+5] cycloaddition reaction, wherein the method uses 1-allyl carbonate-2-olbenzene shown in Formula 1 and an electric-deficient olefin derived from succinic anhydride shown in Formula 2 as raw materials, palladium and a ligand as catalysts, and reacts to obtain a benzo dodecalactone compound shown in Formula 3, and the reaction equation is as follows: in, R is selected from hydrogen, aryl, and alkyl.

2. The preparation method according to claim 1, wherein R is selected from the group consisting of hydrogen atom, phenyl, p-methylphenyl, methyl, ethyl, allyl, and phenylethynyl.

3. The preparation method according to claim 1, wherein the reaction temperature of the method is -10°C to 60°C.

4. The preparation method according to claim 1, wherein the solvent of the method is tetrahydrofuran, dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, or ethyl acetate.

5. The preparation method according to claim 1, wherein the reaction time of the method is 2h-36h.

6. The preparation method according to claim 1, wherein the palladium source is Pd(OAc)2, Pd2(dba)3, and the ligand is PPh3, (4-FPh)3P, (4-CF3Ph)3P, (3-FPh)3P, (4-ClPh)3P.

7. The preparation method according to claim 1, wherein the molar ratio of the 1-allyl carbonate-2-olbenzene 1, the power-deficient olefin 2 derived from succinic anhydride, and the palladium source to the ligand is 1:0.5-2:0.01-0.1:0.04-0.

4.

8. The compound prepared by the preparation method according to claim 1, wherein the compound is selected from:

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